This revised submission of the Clinical Trials Section of the Silvio O. Conte Neuroscience Center for the[unreadable] study of Glutamate Dysregulation in Schizophrenia has been enhanced by a new collaboration with Dr.[unreadable] Daniel Javitt. We will extend findings produced during the first five years and will examine[unreadable] possible explanations for the negative findings of our six month trial with D-cycloserine and the "CONSIST"[unreadable] trial, a 4 month comparison of glycine and D-cycloserine-- neither found effects on negative symptoms or[unreadable] cognition. Because neither D-cycloserine nor glycine may adequing Dr. Javitt's IND, we will conduct a[unreadable] placebo-controlled trial of D-serine a glycine site partial agonist, did not produce siginificant improvement in[unreadable] negative or cognitive symptoms will be followed-up by a new approach in which D-cycloserine is[unreadable] administered once-weekly. This design is intended to avoid tolerance to repeated dosing with D-cycloserine;[unreadable] animal studies and recent studies in patients with phobia indicate that single doses substantially improve[unreadable] cognitive function, but that tolerance develops after approximately two weeks of daily dosing. We[unreadable] will conduct a trial of D-serine co-treatment. This study follows from a previous finding by Tsai and[unreadable] colleagues that the more potent, full agonist D-serine may be effective for positive, negative and cognitive[unreadable] symptoms without evidence for tolerance with repeated dosing. The recent completion of toxicology studies[unreadable] will allow us to obtain an IND for study of D-serine within the next year. In collaboration with Dr. Yurgelun-[unreadable] Todd, we will perform fMRI at baseline and week 8 of the D-serine trial to extend our previous[unreadable] finding of enhanced temporal lobe activation with D-cycloserine which correlated with improvement of[unreadable] negative symptoms. We will expand our collection of DNA samples and our extensive database[unreadable] of phenotypic information from 200 to 500 patients to allow examination of alleles relevant to glutamatergic[unreadable] regulation in relation to clinical characteristics and response to glutamatergic agents. Study of[unreadable] polymorphisms of G72 and D-amino acid oxidase as predictors of D-serine response is one example. We[unreadable] will also further pursue our studies of GCPII by examining two additional polymorphisms in a larger sample.[unreadable] In collaboration with Dr. Yurgelun-Todd, we will also examine NAA/NAAG concentrations in[unreadable] prefrental cortex as a potential biological marker of GCPII activity.